title: Tumor diagnosis with new 111In-radioligands based on truncated human gastrin releasing peptide sequences: synthesis and preclinical comparison.
abstract: Radiolabeled analogs of the frog tetradecapeptide bombesin (BBN) have been proposed for diagnosis and therapy of gastrin releasing peptide receptor (GRPR)-expressing tumors. Following a different and yet unexplored approach, we have developed four novel (111)In-labeled truncated analogs of the human 27-mer GRP after conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) at the N-terminus of GRP(13/14/17/18-27) fragments. Analog affinities for the human GRPR determined against [(125)I-Tyr(4)]BBN were at the nanomolar level and dependent on truncation site. The respective (111)In radioligands specifically internalized in GRPR-expressing PC-3 cells. The shorter chain [(111)In-DOTA]GRP(17/18-27) analogs showed higher metabolic stability in mice. Radioligands specifically localized in human PC-3 xenografts in SCID mice, with [(111)In-DOTA]GRP(17-27) exhibiting the most favorable pharmacokinetic profile. This study has demonstrated the efficacy of human GRP-based radiopeptides to target GRPR-positive lesions in vivo and has revealed the impact of GRP chain length on key biological parameters of resulting radiotracers.
authors.affiliation: Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos" , GR-153 10 Athens, Greece.
authors.forename: Panteleimon J
authors.initials: PJ
authors.lastname: Marsouvanidis
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
authors.forename: Werner
authors.initials: W
authors.lastname: Sallegger
authors.forename: Eric P
authors.initials: EP
authors.lastname: Krenning
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007205:Indium Radioisotopes; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000175:diagnosis*; D018004:Receptors, Bombesin / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D018004:Receptors, Bombesin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid